Ann. N.Y. Acad. Sci.

ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Issue: Annals Meeting Reports

Behavioral epigenetics
Barry M. Lester,1 Edward Tronick,2,3 Eric Nestler,4 Ted Abel,5 Barry Kosofsky,6 Christopher W.
Kuzawa,7 Carmen J. Marsit,8 Ian Maze,9 Michael J. Meaney,10 Lisa M. Monteggia,11 Johannes
M. H. M. Reul,12 David H. Skuse,13 J. David Sweatt,14 and Marcelo A. Wood15
1
Departments of Psychiatry and Human Behavior and Pediatrics, Warren Alpert Medical School, Brown University, Women
and Infants Hospital, Providence, Rhode Island. 2 Department of Psychology, University of Massachusetts, Boston,
Massachusetts. 3 Child Development Unit, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts.
4
Mount Sinai Brain Institute, Department of Neuroscience, Mount Sinai School of Medicine, Fishberg Department of
Neuroscience, Mount Sinai School of Medicine, New York, New York. 5 Department of Biology, University of Pennsylvania,
Philadelphia, Pennsylvania. 6 Divsion of Pediatric Neurology, New York-Presbyterian Hospital/Weill Cornell Medical Center,
New York, New York. 7 Institute for Policy Research, Northwestern University, Evanston, Illinois. 8 Department of Pathology and
Laboratory Medicine, Brown University, Providence, Rhode Island. 9 The Rockefeller University, Laboratory of Chromatin
Biology and Epigenetics, New York, New York. 10 Departments of Psychiatry, Neurology, and Neurosurgery, McGill University,
Montreal, Quebec, Canada. 11 Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas.
12
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom.
13
Behavioural and Brain Sciences Unit, University College of London, Institute of Child Health, London, United Kingdom.
14
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama. 15 Department of Neurobiology
and Behavior, University of California, Irvine, California

Address for correspondence: Barry Lester, Ph.D., Brown Center for the Study of Children at Risk, Women and Infants Hospital,
101 Dudley St., Providence, RI 02908. Barry_Lester@Brown.edu

Sponsored by the New York Academy of Sciences, the Warren Alpert Medical School of Brown University and the
University of Massachusetts Boston, “Behavioral Epigenetics” was held on October 29–30, 2010 at the University of
Massachusetts Boston Campus Center, Boston, Massachusetts. This meeting featured speakers and panel discussions
exploring the emerging field of behavioral epigenetics, from basic biochemical and cellular mechanisms to the epige-
netic modulation of normative development, developmental disorders, and psychopathology. This report provides
an overview of the research presented by leading scientists and lively discussion about the future of investigation at
the behavioral epigenetic level.

Keywords: behavior; epigenetics; chromosome; gene regulation; transcription; methylation

epigenetics. Behavioral epigenetics was described as

Background and perspectives
What is behavioral epigenetics?
Barry M. Lester (Alpert Medical School of Brown
University) introduced the topic of the conference,
behavioral epigenetics, by describing research on the
developmental origins of adult diseases, suggesting
that the fetus is actually making adaptations through
programming to “prepare” for the postnatal en-
vironment in response to environmental signals.
These effects are due, in part, to epigenetic mech-
anisms, raising the fascinating question of whether
these mechanisms can also explain behavioral out-
comes, thus providing an example of the kind of
research that could lead to a new field—behavioral
the application of the principles of epigenetics to
the study of physiological, genetic, environmental,
and developmental mechanisms of behavior in hu-
man and nonhuman animals. Investigations typi-
cally focus at the level of chemical changes, gene
expression, and biological processes that underlie
normal and abnormal behavior. This includes how
behavior affects and is affected by epigenetic pro-
cesses. Interdisciplinary in its approach, it draws
on sciences, such as neuroscience, psychology and
psychiatry, genetics, biochemistry, and psychophar-
macology. Whereas there are thousands of studies of
epigenetics that have been conducted over the last 40
years, the application of epigenetics to the study of

doi: 10.1111/j.1749-6632.2011.06037.x
14 Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
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Lester et al.
Figure 1. The figure shows the 96 articles on behavioral epigenetics grouped by the behavioral construct studied and the genes
that were studied in each of the behavioral construct categories.
behavior is just beginning. A literature search of ci-
tations found only 96 articles to date on behavioral
epigenetics (see Appendix). These articles were an-
alyzed according to the behavioral construct that
was studied (e.g., substance use, psychiatric ill-
ness, learning/memory, neurodevelopment, parent-
ing, stress, and neurodegenerative disorders), the
species studied (e.g., human, mouse, rat), the tissue
that was analyzed (e.g., brain, blood), the epigenetic
mechanisms that were studied (e.g., methylation,
histone modifications), and the particular genes in-
vestigated (Fig. 1). For example, in relation to par-
enting, the most commonly studied genes were the
glucocorticoid receptor and FOS genes. The presen-
tation concluded with cautionary notes about the
unique issues involved in the study of behavioral
epigenetics in humans.
Epigenetics: basic processes and
mechanisms
Eric Nestler (Mount Sinai School of Medicine) pre-
sented an overview of basic epigenetic processes
and mechanisms.1,2 A broad perspective of epige-
netics includes any structural adaptation in chro-
mosomal regions that mediate altered rates of gene
transcription. Epigenetic regulation, also known
as chromatin remodeling, in neurons, describes a
process where the activity of a particular gene is
controlled by the structure of chromatin in that
gene’s proximity (Fig. 2). Chromatin remodeling
is complex, involving multiple covalent modifica-
tions of histones (e.g., acetylation, phosphorylation,
Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
c 2011 New York Academy of Sciences.
Behavioral epigenetics
methylation), ATPase-containing protein com-
plexes that move histone oligomers along a strand
of DNA, methylation of DNA, and the binding of
numerous transcription factors and transcriptional
coactivators and corepressors, all of which act in
a concerted fashion to determine the activity of a
given gene. Epigenetic regulation is crucial for ner-
vous system development. Specifically, it can help
elucidate how genes are affected by environmen-
tal stimuli, including several common mental retar-
dation syndromes and related neurodevelopmen-
tal disorders that are caused by abnormalities in
chromatin-remodeling mechanisms.
Epigenetic regulation also occurs in the mature,
fully differentiated brain and provides unique mech-
anisms that may underlie the stable changes in
gene expression under both normal conditions (e.g.,
learning and memory) and in several pathological
states (e.g., depression, drug addiction, schizophre-
nia, and Huntington’s disease, among others). In
some rare cases (e.g., gene imprinting), epige-
netic modifications can be transmitted to offspring,
which raises the possibility that behavioral experi-
ence in adult life might influence gene expression in
subsequent generations. However, there has not yet
been definitive evidence for epigenetic transmission
of behavioral experience. While work on epigenetic
mechanisms in the brain is still in early stages, it
promises to improve our understanding of brain
plasticity, the pathophysiology of neuropsychiatric
disorders, and may lead to the development of fun-
damentally new treatments for these conditions.
15
Behavioral epigenetics Lester et al.

Figure 2. General scheme of chromatin remodeling. (A) DNA double helix wrapped around an octomer of histone proteins
forming the unit of chromatin, the nucleosome. (B) Chromatin can be conceptualized as existing in two primary structural states:
as active, or open, euchromatin in which histone acetylation opens up the nucleosome to allow binding of the basal transcriptional
complex and other activators of transcription; or as inactive, or condensed, heterochromatin, where all gene activity is permanently
silenced. In reality, chromatin exists in a continuum of several functional states (active, permissive, repressed, and inactivated).
Enrichment of histone modifications, such as acetylation (A) and methylation (M) at histone N-terminal tails and related binding
of coactivators (Co-Act) or repressors (Rep), to chromatin modulates the transcriptional state of the nucleosome.

Epigenetics, intergenerational inertia, and
human adaptation
Christopher W. Kuzawa (Northwestern University)
explored the importance of the dynamic nature of
epigenetic change as a means by which organisms
adapt to environmental change.3,4 He emphasized
that organisms must cope with everything from very
rapid and acute fluctuations (e.g., overnight fast
followed by breakfast) to chronic conditions that
change only gradually (e.g., ice ages or migrating to a
new environment). A range of adaptive mechanisms
allows human populations to adjust to these various

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Lester et al. Behavioral epigenetics

timescales of change (Fig. 3). Natural selection sifts
through the gene pool to select gene variants well
suited to the most stable features of local ecologies.
Rapid and reversible homeostatic processes lie at
the other extreme, maintaining internal constancy
against a backdrop of dynamic environmental con-
ditions, such as food intake or psychosocial stress.
He noted the adaptive importance of developmental
plasticity or the capacity grounded in epigenetic and
other changes that allows a single genome to create
a range of possible traits in interaction with the en-
vironment (e.g., growing larger lungs when raised
at high altitude). Because organisms only develop
once, changing development in response to envi-
ronmental conditions is generally an irreversible
process; thus, developmental plasticity is a suitable
mode of adaptation to environmental features that
are too chronic to be buffered by homeostasis, but
that are also too transient for genetic adaptations to
consolidate around.
Kuzawa pointed out that many documented ex-
amples of epigenetic sensitivity involve the adoption
of stable changes in gene regulation in response to
experiences during limited, early stages of devel-
opment (sensitive periods). Might it make adaptive
sense for a long-lived species like humans to commit
to a strategy for life so early in the life cycle? Lim-
iting epigenetic sensitivity to early developmental
windows may, in fact, create opportunities to ad-
just biology to more reliable environmental cues in
the form of the mother’s own phenotype. Exam-
ples that suggest an ability of the current generation
to entrain development to maternal characteristics
that reflect her cumulative experiences include the
setting of infant growth rate to breast milk leptin
as a cue of maternal energetic history, and work
in the Philippines suggesting that fetal growth may
be calibrated to a woman’s cumulative nutritional
experiences across her lifetime. In both examples,
offspring developmental biology is not sensitive to
potentially transient (and thus unreliable) condi-
tions during the brief period of pregnancy or lacta-
tion. Rather, the maternal resources and signals that
are transferred to offspring may be more integrative
and cumulative in nature and, thus, potentially pro-
vide a more reliable basis for adaptive adjustment.
Kuzawa hypothesized that the timing of early sensi-
tive periods, during which many epigenetic settings
are established, may be more than accidental, but
reflect the evolution of a conduit of sorts, allowing
nongenomic information to be transferred between
generations.
Learning and memory
The second session, moderated by J. David Sweatt
(University of Alabama at Birmingham), served as
an overview of the roles for epigenetic mechanisms
in long-term learning and memory processes and
highlights one of the most exciting contemporary
areas in the behavioral epigenetics field. The ses-
sion was comprehensive in scope, covering cogni-
tion and behavior, synaptic function and cellular

Figure 3. The timescales of human adaptability. Light gray, more rapidly responsive/less durable; black, slowest to respond/most
durable. Epigenetic changes contribute to multiple modes of adaptation, including developmental and intergenerational processes
that allow adjustment to gradual environmental change occurring on a decadal or multigenerational timescale. Modified after
Kuzawa’s work.4

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c 2011 New York Academy of Sciences. 17
Behavioral epigenetics Lester et al.

Figure 4. Schematic representation of epigenetic modifications. (A) In the nucleus, DNA coils and condenses around histones.
Each octameric histone core contains two copies each of histones H2A, H2B, H3, and H4. The DNA–protein complex is referred to
as chromatin. (B) The DNA-histone interaction occurs at the N-terminal tail of a histone, where, for example, on the H3 N-terminal
tail, there are several sites for epigenetic marking via acetylation, methylation, and phosphorylation. (C) In and around gene
promoters that are rich in cytosine-guanine nucleotides (CpG islands), methyl groups are transferred to CpG sites. This process,
called DNA methylation, is catalyzed by a class of enzymes known as DNA methyltransferases.

plasticity, biochemical signaling mechanisms, and
molecular epigenetic mechanisms. The work de-
scribed largely emphasized the specific epigenetic
mechanisms of histone posttranslational modifica-
tion and DNA methylation.
Epigenetic mechanisms in memory formation
Sweatt addressed the idea that conservation of epi-
genetic mechanisms for information storage rep-
resents a unifying model in biology, with epige-
netic mechanisms being used for cellular memory at
levels from behavioral memory to development to
cellular differentiation.5,6 As background, Sweatt
discussed how DNA methylation and histone mod-
ifications are the two most extensively investigated
epigenetic mechanisms. As Sweatt described, until
recently it was thought that once laid down, these
epigenetic marks would remain unchanged for the
lifetime of the organism; recent studies, however, in-
cluding those from the Sweatt laboratory, have chal-
lenged this view. Nevertheless, it is clear that DNA
methylation and attendant changes in chromatin
structure are capable of self-regeneration and self-
perpetuation, necessary characteristics for a stable
molecular mark. Thus, Sweatt discussed the broad
hypothesis that DNA methylation marks can be
modified in response to an organism’s experience
and that these marks play a role in dynamically reg-
ulating the gene transcription supporting synap-
tic plasticity and long-term memory formation and
maintenance (Fig. 4).
Sweatt’s presentation also described several pieces
of evidence supporting the idea that DNA methy-
lation plays a role in memory function in the
adult central nervous system (CNS).6 Thus, he
described how general inhibitors of DNA methyl-
transferase (DNMT) activity alter DNA methyla-
tion in the adult brain and alter the DNA methyla-
tion status of the plasticity-promoting genes reelin
and bdnf. Additional studies demonstrated that de
novo DNMT expression is upregulated in the adult
rat hippocampus after contextual fear conditioning
and that blocking DNMT activity blocks contex-
tual fear conditioning. In addition, results were pre-
sented demonstrating that fear conditioning is as-
sociated with rapid methylation and transcriptional
silencing of the memory suppressor gene protein
phosphatase 1 (PP1) and demethylation and tran-
scriptional activation of the plasticity gene reelin.
These findings have the surprising implication that

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Lester et al. Behavioral epigenetics

Figure 5. HDAC3 modulates memory formation in a Nr4a2-dependent manner. (A) HDAC3-FLOX mice with dorsal hippocampal
deletion of Hdac3 exhibit significantly enhanced long-term memory as compared to wild-type littermates (both groups received
RISC free control). In contrast, siRNA-Nr4a2–treated HDAC3-FLOX mice exhibit no enhanced memory. (B) qRT-PCR shows that
siRNA against Nr4a2 significantly reduces Nr4a2 expression in both HDAC3-FLOX and wild-type littermates.

both active DNA methylation and active demethy-
lation might be involved in long-term memory con-
solidation in the adult CNS.
Finally, a recent series of studies were described5
that found that the bdnf gene locus is also sub-
ject to memory-associated changes in DNA methy-
lation, and, moreover, that this effect is regulated
by the NMDA receptor. Data were also presented
indicating that neuronal DNMT-deficient animals
have deficits in contextual fear conditioning, the
Morris maze learning task, and hippocampal long-
term potentiation (LTP). Overall, Sweatt concluded
that DNA methylation is dynamically regulated in
the adult CNS in response to experience and that
this cellular mechanism is a crucial step in memory
formation.
Chromatin-modifying enzymes in long-term
memory
In the second presentation of the session, Marcelo
A. Wood (University of California, Irvine) dis-
cussed the role of chromatin-modifying enzymes in
regulating gene expression required for long-term
memory formation. Why are chromatin-modifying
enzymes needed to regulate gene expression? A sim-
plistic answer comes from the level that compaction
genomic DNA undergoes when being compressed
to fit into a nucleus. Genomic DNA is two me-
ters in length, yet has to fit into a six-micron nu-
cleus, and, thus, must undergo an approximately
10,000-fold compaction. This generates an access
and indexing problem, which is solved in part by
chromatin-modifying enzymes. The best-studied
chromatin-modifying enzymes in the field of learn-
ing and memory are histone-modifying enzymes,
especially histone acetyltransferases (HATs) and his-
tone deacetylases (HDACs) (Fig. 5).
In the first part of his talk, Wood presented his
lab’s research in examining the role of the CREB-
binding protein (CBP), a potent HAT and transcrip-
tional coactivator, in long-term memory. One lim-
itation in studying the role of CBP in learning and
memory has been the lack of genetically modified
mice with sufficient spatial and temporal regulation.
The Wood lab used genetically modified CBP-FLOX
mice, in combination with adeno-associated virus
(AAV)–expressing Cre recombinase, to generate ho-
mozygous focal Cbp deletions in only area CA1 of
the dorsal hippocampus. This novel approach re-
sulted in the necessary spatial restriction to study
the role of CBP in one brain region and its effect
on long-term memory; additionally, it provided the
temporal restriction to study a homozygous deletion
of Cbp in adult mice, which avoids confounds from
developmental or performance issues. The Wood
lab found that homozygous deletions of Cbp re-
sulted in hippocampus-dependent long-term mem-
ory impairments associated with decreased levels of
specific histone modifications and decreased gene
expression.7
In the second part of his talk, Wood presented
research examining the role of a specific HDAC in
long-term memory formation. To date, the func-
tion of HDAC3, one of the most highly expressed
class I HDACs in the brain, has never been ex-
amined. Again, using AAV-expressing Cre recombi-
nase and HDAC3-FLOX genetically modified mice,
the Wood lab demonstrated that HDAC3 is a key

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c 2011 New York Academy of Sciences. 19
Behavioral epigenetics
negative regulator of long-term memory forma-
tion in the hippocampus. Homozygous deletion
of Hdac3 in area CA1 of the hippocampus led to
enhanced long-term memory associated with in-
creased levels of specific histone modifications and
increased gene expression. Similar results were ob-
served when an HDAC3 selective inhibitor, called
RGFP136, was site specifically delivered to the dorsal
hippocampus. Together, the genetic and pharmaco-
logic data demonstrated that HDAC3 is a negative
regulator of long-term memory formation.8
In summary, Wood posited that HDACs represent
a type of molecular brake pad that is normally en-
gaged but transiently removed by sufficient activity-
dependent signaling to regulate the transcription
required for long-term memory formation.9 Wood
concluded by suggesting that this process may rep-
resent a molecular mechanism to explicate why we
do not encode everything we experience into long-
term memory. Moreover, impaired function of these
molecular brake pads may be associated with disor-
ders including drug addiction and posttraumatic
stress disorder.
Signaling and epigenetic mechanisms
in stress-related memory formation
In the final presentation, Johannes (Hans) Reul
(University of Bristol, UK) presented a novel mech-
anism that may explain why we make such strong
memories of psychologically stressful and emotional
events in our lives. The mechanism he proposed
involves crosstalk between different signaling path-
ways influencing epigenetic processes in neurons of
the hippocampus, a limbic brain region involved in
learning and memory. Stressful events, for example,
a domestic dispute or a job interview, or in ani-
mals, an attack by a predator, evoke the secretion of
glucocorticoid hormones from the adrenal gland.
Classically, these hormones regulate metabolic and
other physiological processes that enable an individ-
ual to cope with the challenge in the best possible
way.
Reul reported, however, that research spanning
the last 25 years has provided evidence that gluco-
corticoids secreted during a psychologically stressful
challenge enhance the consolidation of memories
related to the event—a long-standing observation
that has remained unexplained until now. A finding
made in the 1980s by de Kloet’s group10 pointed to
the dentate gyrus, the gateway of the hippocampus,
20 Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
Lester et al.
as a site of action for glucocorticoids in stress-related
memory formation.
In his presentation, Reul showed that the hor-
mone’s action required distinct epigenetic modifi-
cations of the chromatin: the phosphorylation of
serine10 (S10), in combination with the acetylation
of lysine14 (K14) of histone H3 (H3S10p-K14ac),
leading to the induction of the immediate-early
genes c-Fos and Egr-1 in dentate gyrus granule neu-
rons in rats and mice in vivo.11,12 As the gluco-
corticoid receptor (GR) cannot bring about these
histone modifications directly, Reul suggested that
the GR acts indirectly via interaction with other sig-
naling molecules. More specifically, he postulated
that GR interacts with the NMDA receptor-activated
ERK (extracellular signal-regulated kinase) MAPK
(mitogen-activated protein kinase) signal pathway,
which has a marked role in learning and memory
processes (Fig. 6; Refs. 12 and 13). Supporting this
notion, Reul presented unpublished in vivo data
clearly showing that in activated dentate granule
neurons, that is, those exhibiting phosphorylated
ERK1/2 (pERK1/2), GRs are required to activate
the downstream histone-modifying enzymes MSK1
(mitogen and stress-activated kinase 1), and Elk-1
(Ets-like protein-1) (Fig. 6; Refs. 12–14).
Reul went on to describe pMSK1, a kinase that
can phosphorylate histone H3 at serine10, whereas
pElk-1 binds the HAT p300, which can acetylate his-
tone tails. Further, showing a series of immunoflu-
orescence images, he demonstrated that, during the
consolidation phase of memory formation, all par-
ticipating signaling molecules (pERK1/2, pMSK1,
pElk-1), modified histone molecules (H3S10p-
K14ac), and induced intermediate-early gene
products (c-Fos, Egr-1) can be found in the same
dentate gyrus granule neurons.12,13 Furthermore,
he showed that blocking GRs led to a substan-
tially decreased formation of pMSK1 and pElk-1,
but not pERK1/2, in dentate granule neurons af-
ter forced swim stress.12 He concluded that stress-
ful events are strongly encoded into memory be-
cause of the marked activating role of GRs on ERK
MAPK, signaling to the chromatin in dentate gyrus
neurons (Fig. 6; Ref. 12). These findings may be of
significance for stress-related psychiatric disorders,
such as major depression and anxiety, including
PTSD.
The formal presentations were followed by a
wide-ranging and lively discussion of the roles
c 2011 New York Academy of Sciences.
Lester et al. Behavioral epigenetics

Figure 6. Glucocorticoid hormones, secreted as a result of a stressful event, enhance the consolidation of behavioral responses,
including memories related to the event. Until recently, the underlying mechanisms of these effects were unknown. Recent
work of the Reul group at the University of Bristol shows that glucocorticoids act by binding to glucocorticoid receptors (GRs)
that interact with the NMDA receptor-activated ERK1/2/MSK1-Elk-1 signaling pathway enhancing the formation of epigenetic
modifications (i.e., the serine10 phosphorylation and lysine14 acetylation in histone H3 (H3S10p-K14ac)) and the induction of the
neuroplasticity-associated immediate-early genes c-Fos and Egr-1 in sparsely distributed mature dentate gyrus neurons. Evidence
has been accumulating that these signaling, epigenetic, and genomic phenomena are of critical importance for the consolidation of
memories related to the endured stressful event.

and regulation of epigenetic mechanisms in long- Alterations of DNA methylation, growth

term synaptic plasticity and behavioral memory
in vivo.
Development
This section, chaired by Edward Tronick (Univer-
sity of Massachusetts Boston and Children’s Hospi-
tal Boston), focused on the emerging environmental
epigenetics hypothesis, which suggests that environ-
mental signals operate during early development to
alter epigenetic marks across the genome, thus in-
fluencing neural development and function.
restriction, and infant neurobehavior
The first talk was by Carmen J. Marsit (Brown Uni-
versity) and focused on altered epigenetic marks
within the placenta. Epidemiological studies iden-
tify variations in birth weight as a predictor of health
over the lifespan, including the risk for neuropsy-
chiatric disorders.15 Marsit discussed a novel way
in which to consider the effects of the intrauter-
ine environment on infant neurodevelopment in
human populations, focusing on how differences
in DNA methylation at specific genomic regions
in the human placenta are associated with infant

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c 2011 New York Academy of Sciences. 21
Behavioral epigenetics
neurobehavior. The placenta acts as the master reg-
ulator of the intrauterine environment, not only
through nutrients, gas, water, and waste exchange,
but also through the production of pregnancy-
related hormones, proteins, and growth factors, in-
cluding neuropeptide hormones analogous to those
produced by the hypothalamus and pituitary. Fi-
nally, the placenta also acts as a barrier commonly
metabolizing maternal hormones to inactive forms
and, thus, stabilizing the intrauterine endocrine en-
vironment. Such considerations have led to the con-
cept that the placenta acts as the “third brain” by
linking the developed maternal physiological state
with the developing fetus.
Importantly, placental gene expression is subject
to environmental regulation. Marsit’s group con-
sidered how changes to the patterns of DNA methy-
lation in the placenta may alter the function of the
placenta in these critical roles and, in turn, how these
alterations manifest in neurobehavioral phenotypes
in infants, characterized using the well-established
Neonatal Intensive Care Unit Network Neurobehav-
ioral Scales (NNNS).
Marsit highlighted work linking patterns of DNA
methylation in the placenta to the intrauterine en-
vironment represented by infant growth, showing
strong and significant associations between profiles
of DNA methylation, identified using genome-wide
array-based approaches, and infant birth weight.16
He went on to demonstrate that increasing methy-
lation of the human GR 1F was strongly and sig-
nificantly associated with decreased measures of
infant attention on the NNNS (Fig. 7). Impor-
tantly, the methylation of an analogous receptor
(rat exon 17 ) in rat pup hippocampus has linked
Figure 7. Association between greater than median glucocorticoid receptor exon 1F methylation and infant attention score is
specific to nongrowth restricted infants.
22
Lester et al.
to maternal behaviors (see Meaney presentation
below).
Marsit also showed that these effects were most
pronounced among infants of normal weight for
gestational age, suggesting that there may be normal
variability in placental methylation that accounts
for variation in infant neurobehavior. As Marsit
expands his studies of the role of the intrauterine
environment captured in the placenta epigenome,
links between the methylation of key genes involved
in HPA axis control and infant neurobehavior, and
associations between genome-wide profiles of DNA
methylation and infant neurodevelopment are being
pursued. These studies are of particular importance
as multiple environmental exposures, such as nutri-
ent deprivation, are known to affect infant growth
and are associated with an increased risk for neu-
rocognitive conditions, including attention deficit
hyperactivity disorder (ADHD).
Epigenetic alterations and exposure
to cocaine in utero
Barry Kosofsky (Weill Cornell Medical College) dis-
cussed how developmental brain disorders and the
consequences of prenatal exposure to drugs of abuse
(cocaine, in particular) are associated with sustained
changes in CNS gene expression and have last-
ing consequences for brain structure and function
(Fig. 8).17 Prenatal exposure to toxins, including
substances of abuse, is associated with developmen-
tal effects in children. Kosofsky suggested that such
aberrant effects might be considered “molecular
malformations,” leading to conditions where neural
signaling pathways are rendered dysfunctional. Such
molecular changes may “feed forward” to produce
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Lester et al.
Figure 8. Epigenetic mechanisms underlying persistent alterations on promoters of genes involved in neuronal plasticity.
alterations in the behavioral repertoire of affected
infants, children, and young adults—changes that
are sculpted by environmental interactions. Kosof-
sky’s research explores the hypothesis that the result-
ing molecular maladaptations are, in part, mediated
by epigenetic mechanisms.
Kosofsky presented data from a mouse model
of transplacental cocaine exposure. These findings
suggest that changes are expressed in a gene-specific,
region-specific, and time-specific fashion; when ap-
parent in the medial prefrontal cortex (mPFC), these
changes appear to result in altered structural and
functional maturation of that brain region. When
compared with control animals (i.e., mice with no
prenatal drug exposure), the cocaine-exposed mice
showed a differential pattern of performance on a
social interaction (SI) task: increased SI relative to
controls at P28 (juvenile) and decreased SI relative
to controls as adults. A parallel pattern of expres-
sion of the mRNA for the transcription factor EGR1
(also known as NGF-1a and zif 268) was observed in
mPFC corresponding with these ages. In adult an-
imals, changes in EGR1 expression correlated with
decreased binding of MeCP2 to the EGR1 promoter;
the same pattern was not observed at P28. Vari-
ations in MeCP2 occupancy suggest that an epi-
genetic mechanism may underlie changes in gene
expression and behavior.
Kosofsky presented additional behavioral studies
using an “extinction of conditioned fear” model,
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Behavioral epigenetics
demonstrating that mice exposed to cocaine pre-
natally demonstrated impaired spontaneous recov-
ery of extinction, a form of learning that relies on
the mPFC. The prenatally cocaine-exposed animals
showed a decrease in the binding of MeCP2 to the
promoter of exons I and IV of the bdnf gene, which
was associated with decreased mRNA expression
of those transcripts in mPFC, likewise suggesting
an epigenetic mechanism underlying the behavioral
alterations. These findings are consistent with the
presentation of David Sweatt in an earlier session
on epigenetic mechanisms for learning and mem-
ory that highlighted the importance of epigenetic
regulation of the bdnf gene for fear conditioning.
The implication from these findings is that perina-
tal environmental conditions might determine the
capacity for neural plasticity in later life through
epigenetic regulation of genes critical for synaptic
remodeling. Kosofsky’s group is currently pursuing
“rescue experiments” to further explore the link be-
tween the proposed molecular mechanisms in the
animals prenatally treated with cocaine. The find-
ings may provide an opportunity for translational
benefit regarding the diagnosis and treatment for
the offspring of woman who abuse drugs during
pregnancy.
Epigenetic programming by maternal care
Michael J. Meaney (McGill University) summarized
previous studies showing that variations in maternal
23
Behavioral epigenetics
Figure 9. Tactile stimulation derived from pup LG increases 5-HT activity at the level of the hippocampus, thus increasing NGFI-A
expression and its association with the exon 17 promoter, which then initiates an alteration of the methylation state of the exon 17
glucocorticoid receptor promoter.
care in the rat, specifically in the frequency of pup
licking/grooming (LG), is associated with increased
methylation of the exon 17 GR promoter in the
hippocampus, decreased hippocampal FR expres-
sion, and increased hypothalamic-pituitary-adrenal
(HPA) responses to stress.18,19 Previous work sug-
gests that reversing the effects of differential DNA
methylation of the exon 17 promoter, in turn, can
reverse the effects of maternal care on hippocampal
FR expression and HPA responses to stress. Meaney
also presented findings from studies in the post-
mortem human hippocampus showing that a de-
velopmental history of child abuse was associated
with an increase in the methylation of the exon 1F
GR promoter (also see Marsit summary) and de-
creased GR expression. The focus of the talk con-
cerned the mechanisms by which the environmen-
tal signal, pup LG, might generate the difference
in DNA methylation, and gene expression. Meaney
summarized in vitro and in vivo evidence for the im-
portance of serotonin (5-HT)- and 5-HT–induced
increases in hippocampal NGFI-A expression for the
alterations in the methylation state of the exon 17
promoter. A shRNA targeting NGFI-A blocks both
the effects of 5-HT on the methylation state of the
exon 17 promoter and effects on GR expression. Pup
LG provides tactile stimulation of the pup, resulting
in an increase in circulating levels of triiodoithyro-
nine (T3), the most biologically active thyroid hor-
24
Lester et al.
mone. T3 increases central 5-HT activity in the rat
pup, and its administration is sufficient to increase
the association of NGFI-A with the exon 17 pro-
moter. Pup LG from the mother directly increases
NGFI-A association with the exon 17 promoter, and
artificial tactile stimulation mimics this effect. These
findings suggest that the tactile stimulation derived
from pup LG increases 5-HT activity at the level of
the hippocampus, thus increasing NGFI-A expres-
sion and its association with the exon 17 promoter,
which then initiates an alteration of the methyla-
tion state of the exon 17 GR promoter (Fig. 9).
The results are consistent with previous studies in
vitro showing that overexpression of NGFI-A alters
the methylation of the exon 17 promoter. Interest-
ingly, NGFI-A also regulates the expression of the
GAD1 gene that encodes glutamic acid decaroxy-
lase 1, and maternal care regulates the methylation
of the GAD1 and GAD1 expression in a manner
comparable to that of the GR. These studies are
consistent with earlier reports of alterations in DNA
methylation associated with increased transcription
factor binding, and suggest that environmental con-
ditions can directly alter epigenetic states through
the activation of intracellular signaling pathways.
Meaney also noted important caveats, most notably,
the importance of identifying the enzyme directly
responsible for the alteration in the methylation
state.
Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
c 2011 New York Academy of Sciences.
Lester et al. Behavioral epigenetics

Summary of symposium on development nisms by which drugs of abuse and stress produce
Each of these presentations focused on well- long-lasting alterations in gene expression and be-
established environmental influences, including havior.20 Moreover, identifying common regulatory
pre- and postnatal maternal effects and drugs of mechanisms in cocaine and stress models may aid in
exposure. This research reflects an emerging body the development of therapeutics aimed at alleviating
of science examining epigenetic states as candidate addiction and depression syndromes.
mechanisms that link environmental conditions in
Epigenetic targets in neurodegenerative and
early development with sustained changes in gene
psychiatric disorders
expression and neural development. Predictably, the
Ted Abel (University of Pennsylvania) focused
discussion focused on the enthusiasm for the po-
on another type of crucial histone modification,
tential benefits of interventions targeting epigenetic
namely, histone acetylation, which is generally as-
mechanisms. The speakers noted that the current
sociated with transcriptional activation. Histone
period marks a very early stage for research linking
acetylation is catalyzed by HATs and reversed by
environmental conditions to alterations in gene ex-
HDACs. One of the major HATs present in the brain
pression and brain function. Nevertheless, the trans-
is the transcriptional coactivator, termed CBP. Abel
lational science presented within this symposium
et al. have shown that CBP is involved in synaptic
suggests that epigenetics represents a fruitful area
plasticity in the hippocampus and in specific forms
of research bridging epidemiological findings with
of long-term memory mediated via hippocampal
studies of biological mechanism.
circuits. Thus, mutant mice, in which CBP activ-
Neuropsychiatry ity in neurons is reduced, exhibit deficits in spatial
and contextual memory and in long-lasting forms
Histone methylation in cocaine-induced
of hippocampal synaptic plasticity. A complemen-
behavioral and structural plasticity
tary method to study the role of histone acetylation
Ian Maze presented research from Eric Nestler’s lab-
in synaptic plasticity and memory is to examine the
oratory (Mount Sinai School of Medicine) that di-
effects of HDAC inhibitors, which increase histone
rectly implicates a role for repressive histone methy-
acetylation and transcriptional activation. The Abel
lation, specifically dimethylation of Lys9 on histone
laboratory and other groups have found that ad-
H3 (H3K9me2), in cocaine addiction (Fig. 10).
ministration of an HDAC inhibitor, such as tricho-
Maze et al. have shown that chronic cocaine
statin A, enhances long-term contextual memory
administration to mice reduces global levels of
and facilitates synaptic plasticity via the transcrip-
H3K9me2 in nucleus accumbens (NAc), a key brain
tion factor CREB. Among important target genes
region involved in processing reward and implicated
induced by HDAC inhibition and CREB in the hip-
in addiction.20 In NAc, the reduction in H3K9me2
pocampus are certain nuclear receptor transcription
is mediated through decreased expression of G9a, a
factors that are critical for the enhanced cognitive
histone methyltransferase that specifically catalyzes
ability observed. Histone acetylation may, therefore,
H3K9me2. The repression of G9a, in turn, is me-
provide an epigenetic mechanism for establishing
diated by the cocaine-induced transcription factor,
gene-specific modifications that result in the co-
FosB. Using conditional mutagenesis and viral-
ordinate expression of genes required for long-term
mediated gene transfer, the group found that G9a
memory storage. As well, HDAC inhibitors may pro-
downregulation increases dendritic spine plasticity
vide a novel therapeutic approach to treat the cogni-
of NAc neurons and enhances rewarding responses
tive deficits that accompany many neuropsychiatric
to cocaine by decreasing repressive H3K9me2 at spe-
disorders.
cific target genes and, therefore, increasing those
genes’ expression. Cocaine-induced downregula- Epigenetic mechanisms regulating synapse
tion of G9a and H3K9me2 also promotes an in- function and behavior
dividual’s vulnerability to stressful experiences and Lisa M. Monteggia (The University of Texas South-
the development of depression-like behavioral ab- western Medical Center at Dallas) discussed her lab-
normalities. These findings are consistent with clin- oratory’s studies of loss-of-function mutations in
ical data that drug addiction and depression often the gene methyl-CpG-binding protein-2 (MeCP2)
occur together. This work has defined new mecha- that cause Rett syndrome, a neurodevelopmental

Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 

c 2011 New York Academy of Sciences. 25
Behavioral epigenetics
Figure 10. Mechanism of increased cocaine sensitivity.
disorder characterized by reduced cognitive func-
tion and autism spectrum-like behavioral abnor-
malities, among other deficits.
Monteggia et al., along with other groups, have
demonstrated that mice lacking MeCP2 exhibit ab-
normal cognitive and social behavior. The group
has also demonstrated that loss of MeCP2 de-
creases excitatory glutamatergic transmission in
the hippocampus, primarily by reducing glutamate
release. By contrast, no deficit in inhibitory
GABAergic function is seen. The results suggest
that some Rett abnormalities are caused by an
imbalance between excitatory and inhibitory neu-
rotransmission in particular brain circuits, a possi-
bility supported by work from the Monteggia lab-
oratory. MeCP2, encoded by the X chromosome,
functions predominantly by binding to methylated
CpG islands in the promoter region of certain genes
and thereby silencing those genes’ expression. This
occurs, in part, by forming a protein complex with
HDACs, which also repress gene activation, as noted
above. The Monteggia laboratory has, therefore,
started to investigate the coordinated role of histone
deacetylation and DNA methylation in the regula-
26
Lester et al.
tion of synaptic function. The regulation of these
two key epigenetic mechanisms by synaptic activity,
and how such alterations affect neurotransmission,
will be critical to elucidate the mechanisms under-
lying Rett syndrome as well as the roles these factors
have in basic cellular processes. This work is also
essential in understanding abnormalities in neuro-
transmission that underlie Rett syndrome and other
neuropsychiatric disorders.
Epigenetic risk factors in
social-communication disorders
David H. Skuse (University College London in the
UK) discussed genomic imprinting, which involves
epigenetic modifications that result in differential
gene expression from certain genes (or even entire
chromosomes) that are of paternal versus maternal
origin.
Importantly, Skuse et al. have proposed that
imprinting of the X-chromosome could result in
sexually dimorphic characteristics. This hypothesis
predicts that sexually dimorphic (male) vulnerabil-
ity to some neurodevelopmental disorders, such as
autism, could occur on the basis of whether the
Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
c 2011 New York Academy of Sciences.
Lester et al.
silencing of alleles is confined to chromosomes that
were either paternally or maternally derived.21
The X-chromosome is enriched for genes that
are involved in brain function. X-monosomy in hu-
mans results in Turner syndrome, which provides a
model by which these putative mechanisms can be
studied. In general, studies have shown that females
with a single X-chromosome of paternal origin have
better social communication skills, and are more
empathic, than those whose single X-chromosome
is maternal in origin.22 Autosomal gene expression
may be regulated by X-linked genes.23
Skuse’s laboratory has shown in longitudinal
studies that these differences persist from childhood
into adulthood. These human observations have
more recently been followed-up by studies of X-
monosomic mice. Replicated findings include pref-
erential expression of alleles from the maternally
derived X-chromosome. One particular allele, in-
variably expressed in males, is associated with per-
severative behavior.24 No evidence for preferential
expression of the paternally derived X-chromosome
has yet been observed, although recent work from
Catherine Dulac’s laboratory at Harvard has pro-
vided support for the role of X-linked imprinting in
brain development.25
Better understanding the mechanisms of genomic
imprinting has the potential of providing new in-
sight into the molecular basis of individual variabil-
ity in personality traits as well as features of neu-
ropsychiatric disorders.
Concluding Remarks
This conference brought together cutting-edge an-
imal and human research in the emerging field of
behavioral epigenetics. As exciting as these findings
are, there are a number of challenges that need to
be addressed as the field moves forward. Ed Tronick
(University of Massachusetts and Harvard Medical
School) pointed out that given what is now known
about environmental effects that there needs to be
as much effort put into characterizing the details of
the experience of the animal or human and its envi-
ronment as has gone into characterizing molecular
mechanisms. At the moment experiential and envi-
ronmental “phenotyping” is crude. Even in the best
animal experimental studies, factors in addition to
the study proper, such as housing conditions, events
during animal housing, handling regimes, light cy-
cles, social contacts, to name a few are not well spec-
Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
c 2011 New York Academy of Sciences.
Behavioral epigenetics
ified. Yet any or all of these environmental factors,
and the animals’ engagement with them, may lead
to epigenetic effects. Indeed the presumption of epi-
genetics is that such factors do and will have effects.
For example, the stability of epigenetic changes may
be the result of changes in environmental factors
that function to stabilize, destabilize, or even reit-
eratively induce epigenetic changes rather than the
stability being “inherent” to the epigenetic change
in and of itself. Moreover, the dynamics of change
need to be better understood; that is, epigenetic
changes related specifically to external environmen-
tal events in turn can become causal elements that go
on to amplify, stabilize, or inhibit other epigenetic
changes. These dynamics have come to be appreci-
ated in studies of physiologic systems such as the
HPA axis, where physiologic and behavioral feed-
back and feed-forward loops operating over time are
critical to understanding how the organism func-
tions. Similar dynamic thinking needs to be intro-
duced into our models of epigenetic changes.
Tronick noted that most of the models we have
for epigenetic mechanisms related to behavior are
models of abnormal processes, such as toxic expo-
sures or deprivation. We know less about epigenetic
processes that affect normal behavior as was shown
in work of Marsit. Thus much of what we know
may be related to aberrant processes that fall out-
side the range of normal epigenetic processes. For
example, the finding of high levels of methylation
early in development could suggest that the timing
of the effects of experience may be critical to under-
standing epigenetic effects on behavior. Moreover,
the idea of developmental change as being, in part, a
process related to a release from methylation would
have profound effects for our understanding of de-
velopment, such as identifying the events and their
timing that trigger the release from methylation, as
well as for therapeutic interventions.
Tronick recognized that at the present time our
ability to specify the chain of causality of epigenetic
changes in human behavior is limited because of our
inability to access brain tissue. One can only hope
that new techniques will be developed that overcome
this limitation and that with a better understand-
ing of tissue may lead to the finding of “substitutes
tissue” and correlated changes in other physiologi-
cal systems. For example, epigenetic changes in the
glucocorticoid receptor detected in plasma or buc-
cal cells accompanied by parallel changes in ACTH,
27
Behavioral epigenetics
CRF or cortisol would strengthen the role of the HPA
axis. But while we wait for these new innovations
there needs to be an appreciation of the limitations
of human epigenetic work compared to the research
done on animals. The state of the art of the two areas
is not the same, and applying state-of-the-art animal
standards to human work will only limit progress.
Tracing human behavior to epigenetic changes will
be difficult, but we can make every effort to have
as much detailed characterization of the epigenetic,
physiologic, behavioral, and environmental links as
possible and then to fill in the hidden links with
work using animal models. That said, whatever the
organism, we need to appreciate the full complexity
of epigenetic changes.
Certainly, part of the excitement of this confer-
ence was the coming together of scientists from dif-
ferent disciplines, such as molecular biologists and
behavioral scientists, who are capable of developing
models that will elucidate both the hidden links and
the complexity to further advance this relatively new
field of behavioral epigenetics.
Acknowledgments
The Behavioral Epigenetics conference was pre-
sented by the New York Academy of Sciences, the
Warren Alpert Medical School of Brown Univer-
sity, and the University of Massachusetts Boston,
and supported in part by the University of Mas-
sachusetts Boston and the Life TechnologiesTM
Foundation (Silver), the Massachusetts Life Sciences
Center (Bronze), and Bristol-Myers Squibb R&D
and Genomatix Software, Inc (Academy Friends).
Funding for this conference was also made possi-
ble by (i) Grant 1 R13 DA029985-01 from the Na-
tional Institute on Drug Abuse, the Eunice Kennedy
Shriver National Institute of Child Health and Hu-
man Development, the National Institute of Mental
Health, and the National Institutes of Health, Office
of the Director (Barry M. Lester, Principal Investiga-
tor); (ii) an Independent Medical Education Grant
from AstraZeneca; (iii) March of Dimes Founda-
tion Grant No. 4-FY10-458; and (iv) an educational
grant from Janssen, a division of Ortho-McNeil-
Janssen Pharmaceuticals, Inc., administered by
Ortho-McNeil-Janssen Scientific Affairs, LLC.
Conflicts of interest
The author declares no conflicts of interest.
28 Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
Lester et al.
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30 Ann. N.Y. Acad. Sci. 1226 (2011) 14–33 
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